As an innovative dosage form, traditional Chinese medicine(TCM) dry powder inhalers have emerged as a focal point in the research and development of new preparations due to its high efficiency, safety, and bioavailability. This paper systematically reviewed the relevant literature and patents associated with TCM dry powder inhalers to analyze the origins and the current research and development status. Furthermore, this paper probed into the research and development ideas of TCM dry powder inhalers regarding clinical positioning, prescription screening, and druggability. Additionally, the paper thoroughly analyzed the technical barriers in druggability studies and elaborated on corresponding research techniques and coping measures. Furthermore, it emphasized the need for improved regulations and policies governing TCM dry powder inhalers, advocated for strengthened oversight, and called for the establishment of a scientific quality evaluation system. Measures such as promoting production-education-research collaboration, enhancing personnel training, and fostering international exchanges were proposed to provide a scientific and systematic reference for the future research, development, and application of TCM dry powder inhalers, thereby facilitating the rapid modernization of TCM.
Humans ; Dry Powder Inhalers/trends* ; Drugs, Chinese Herbal/chemistry* ; Medicine, Chinese Traditional/instrumentation* ; Administration, Inhalation

PURPOSE: The fixation method commonly employed worldwide for treating unstable fractures of the posterior pelvic ring is the percutaneous iliosacral screw technique. However, prolonged operation time and frequent fluoroscopies result in surgical risks. This study aimed to investigate whether a new triangulation method could reduce operative and fluoroscopy times and increase the accuracy of screw placement. METHODS: This study is a real-world retrospective cohort analysis that examined a patient cohort who underwent percutaneous iliosacral screw fixation between January 1, 2019 and December 31, 2022. Inclusion criteria were patients (1) diagnosed with posterior pelvic ring instability who underwent pelvic fracture closed reduction and percutaneous S1 transverse-penetrating iliosacral screw placement and (2) aged >18 years. Exclusion criteria were: (1) combined proximal femoral fractures, (2) severe soft tissue injury in the surgical area, (3) incomplete imaging data, and (4) declining to provide written informed consent by the patient. The patients were divided into 2 groups according to the screw insertion method: conventional and triangulation methods. Screw placement and fluoroscopy times recorded by the C-arm were compared between the 2 methods. The accuracy of screw placement was evaluated by Smith grading on postoperative CT. Normality tests were conducted to assess the distribution of the quantitative variables and the Chi-square test was used to compare the qualitative variables. RESULTS: The study included a total of 94 patients diagnosed with posterior pelvic ring instability, who underwent percutaneous iliosacral screw placement. The patients were divided into 2 groups: 46 patients treated with the conventional surgical method and 48 patients received the triangulation method. The operation time (61.13±9.69 vs. 35.77±6.27) min and fluoroscopy frequency times (52.15±9.29 vs. 24.40±4.04) of the triangulation method were significantly reduced (p<0.001). CONCLUSIONS The use of a triangular positioning technique for the surface positioning of percutaneous iliosacral screws could reduce the operative time and fluoroscopy frequency. And the screw placement accuracy using this new method was comparable to that using other conventional methods.
Humans ; Retrospective Studies ; Bone Screws ; Pelvic Bones/surgery* ; Male ; Female ; Fracture Fixation, Internal/methods* ; Fractures, Bone/surgery* ; Adult ; Middle Aged ; Fluoroscopy ; Aged ; Sacrum/surgery* ; Operative Time

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia in the elderly. This study aimed to evaluate urban-rural disparities in its prevalence and management in elderly Chinese. METHODS: Consecutive participants aged ≥ 65 years attending outpatient clinics were enrolled for AF screening using handheld single-lead electrocardiogram (ECG) from April 2017 to December 2022. Each ECG rhythm strip was reviewed from the research team. AF or uninterpretable single-lead ECGs were referred for 12-lead ECG. Primary study outcome comparison was between rural and urban areas for the prevalence of AF. The Student's t-test was used to compare mean values of clinical characteristics between rural and urban participants, while the Pearson's chi-square test was used to compare between-group proportions. Multivariate stepwise logistic regression analysis was performed to estimate the association between AF and various patient characteristics. RESULTS: The 29,166 study participants included 13,253 men (45.4%) and had a mean age of 72.2 years. The 7073 rural participants differed significantly (P ≤ 0.02) from the 22,093 urban participants in several major characteristics, such as older age, greater body mass index, and so on. The overall prevalence of AF was 4.6% (n = 1347). AF was more prevalent in 7073 rural participants than 22,093 urban participants (5.6% vs. 4.3%, P < 0.01), before and after adjustment for age, body mass index, blood pressure, pulse rate, cigarette smoking, alcohol consumption and prior medical history. Multivariate logistic regression analysis identified overweight/obesity (OR = 1.35, 95% CI: 1.17-1.54) in urban areas and cigarette smoking (OR = 1.62, 95% CI: 1.20-2.17) and alcohol consumption (OR = 1.42, 95% CI: 1.04-1.93) in rural areas as specific risk factors for prevalent AF. In patients with known AF in urban areas (n = 781) and rural areas (n = 338), 60.6% and 45.9%, respectively, received AF treatment (P < 0.01), and only 22.4% and 17.2%, respectively, received anticoagulation therapy (P = 0.05). CONCLUSIONS In China, there are urban-rural disparities in AF in the elderly, with a higher prevalence and worse management in rural areas than urban areas. Our study findings provide insight for health policymakers to consider urban-rural disparity in the prevention and treatment of AF.

Alzheimer's disease (AD) is the major form of dementia in the elderly and is closely related to the toxic effects of microglia sustained activation. In AD, sustained microglial activation triggers impaired synaptic pruning, neuroinflammation, neurotoxicity, and cognitive deficits. Accumulating evidence has demonstrated that aberrant expression of deubiquitinating enzymes is associated with regulating microglia function. Here, we use RNA sequencing to identify a deubiquitinase YOD1 as a regulator of microglial function and AD pathology. Further study showed that YOD1 knockout significantly improved the migration, phagocytosis, and inflammatory response of microglia, thereby improving the cognitive impairment of AD model mice. Through LC-MS/MS analysis combined with Co-IP, we found that Myosin heavy chain 9 (MYH9), a key regulator maintaining microglia homeostasis, is an interacting protein of YOD1. Mechanistically, YOD1 binds to MYH9 and maintains its stability by removing the K48 ubiquitin chain from MYH9, thereby mediating the microglia polarization signaling pathway to mediate microglia homeostasis. Taken together, our study reveals a specific role of microglial YOD1 in mediating microglia homeostasis and AD pathology, which provides a potential strategy for targeting microglia to treat AD.

This study aimed to comprehensively examine the association of gallstones, cholecystectomy, and cancer risk. Multivariable logistic regressions were performed to estimate the observational associations of gallstones and cholecystectomy with cancer risk, using data from a nationwide cohort involving 239 799 participants. General and gender-specific two-sample Mendelian randomization (MR) analysis was further conducted to assess the causalities of the observed associations. Observationally, a history of gallstones without cholecystectomy was associated with a high risk of stomach cancer (adjusted odds ratio (aOR)=2.54, 95% confidence interval (CI) 1.50-4.28), liver and bile duct cancer (aOR=2.46, 95% CI 1.17-5.16), kidney cancer (aOR=2.04, 95% CI 1.05-3.94), and bladder cancer (aOR=2.23, 95% CI 1.01-5.13) in the general population, as well as cervical cancer (aOR=1.69, 95% CI 1.12-2.56) in women. Moreover, cholecystectomy was associated with high odds of stomach cancer (aOR=2.41, 95% CI 1.29-4.49), colorectal cancer (aOR=1.83, 95% CI 1.18-2.85), and cancer of liver and bile duct (aOR=2.58, 95% CI 1.11-6.02). MR analysis only supported the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer. This study added evidence to the causal effect of gallstones on stomach, liver and bile duct, kidney, and bladder cancer, highlighting the importance of cancer screening in individuals with gallstones.
Humans ; Mendelian Randomization Analysis ; Gallstones/complications* ; Female ; Male ; Cholecystectomy/statistics & numerical data* ; Middle Aged ; Risk Factors ; Aged ; Adult ; Neoplasms/etiology* ; Stomach Neoplasms/epidemiology*

OBJECTIVE: Gastric cancer (GC) is one of the most common malignancies seen in clinic and requires novel treatment options. Morin is a natural flavonoid extracted from the flower stalk of a highly valuable medicinal plant Prunella vulgaris L., which exhibits an anti-cancer effect in multiple types of tumors. However, the therapeutic effect and underlying mechanism of morin in treating GC remains elusive. The study aims to explore the therapeutic effect and underlying molecular mechanisms of morin in GC. METHODS: For in vitro experiments, the proliferation inhibition of morin was measured by cell counting kit-8 assay and colony formation assay in human GC cell line MKN45, human gastric adenocarcinoma cell line AGS, and human gastric epithelial cell line GES-1; for apoptosis analysis, microscopic photography, Western blotting, ubiquitination analysis, quantitative polymerase chain reaction analysis, flow cytometry, and RNA interference technology were employed. For in vivo studies, immunohistochemistry, biomedical analysis, and Western blotting were used to assess the efficacy and safety of morin in a xenograft mouse model of GC. RESULTS: Morin significantly inhibited the proliferation of GC cells MKN45 and AGS in a dose- and time-dependent manner, but did not inhibit human gastric epithelial cells GES-1. Only the caspase inhibitor Z-VAD-FMK was able to significantly reverse the inhibition of proliferation by morin in both GC cells, suggesting that apoptosis was the main type of cell death during the treatment. Morin induced intrinsic apoptosis in a dose-dependent manner in GC cells, which mainly relied on B cell leukemia/lymphoma 2 (BCL-2) associated agonist of cell death (BAD) but not phorbol-12-myristate-13-acetate-induced protein 1. The upregulation of BAD by morin was due to blocking the ubiquitination degradation of BAD, rather than the transcription regulation and the phosphorylation of BAD. Furthermore, the combination of morin and BCL-2 inhibitor navitoclax (also known as ABT-737) produced a synergistic inhibitory effect in GC cells through amplifying apoptotic signals. In addition, morin treatment significantly suppressed the growth of GC in vivo by upregulating BAD and the subsequent activation of its downstream apoptosis pathway. CONCLUSION Morin suppressed GC by inducing apoptosis, which was mainly due to blocking the ubiquitination-based degradation of the pro-apoptotic protein BAD. The combination of morin and the BCL-2 inhibitor ABT-737 synergistically amplified apoptotic signals in GC cells, which may overcome the drug resistance of the BCL-2 inhibitor. These findings indicated that morin was a potent and promising agent for GC treatment. Please cite this article as: Wang Y, Sun XY, Ma FQ, Ren MM, Zhao RH, Qin MM, Zhu XH, Xu Y, Cao ND, Chen YY, Dong TG, Pan YF, Zhao AG. Morin inhibits ubiquitination degradation of BCL-2 associated agonist of cell death and synergizes with BCL-2 inhibitor in gastric cancer cells. J Integr Med. 2025; 23(3): 320-332.
Humans ; Flavonoids/therapeutic use* ; Stomach Neoplasms/pathology* ; Animals ; Proto-Oncogene Proteins c-bcl-2/metabolism* ; Cell Line, Tumor ; Apoptosis/drug effects* ; Cell Proliferation/drug effects* ; Ubiquitination/drug effects* ; Mice ; Drug Synergism ; Mice, Inbred BALB C ; Mice, Nude ; Xenograft Model Antitumor Assays ; Flavones

Objective To explore the effect of Huoxue Xiaoyi Formula on ovarian function and pregnancy outcome in endometriosis rats. Methods One hundred female SD rats were fed adaptively for 7 days. According to body weight, 98 rats with a normal estrous cycle were randomly divided into the blank group (n=14), the sham operation group (n=14), the donor group (n=12), and the receptor group (n=58). A rat model of endometriosis was established using allogeneic endometrial transplantation. After the model was successfully established, according to the body weight, 56 rats in the receptor group were randomly divided into the model group, and the Huoxue Xiaoyi Formula low-, medium-, and high-dose groups, with 14 rats in each group. The Huoxue Xiaoyi Formula low-, medium-, and high-dose groups were given 5.86, 11.72, and 23.44 g/kg of Huoxue Xiaoyi Formula, and the blank group, the sham operation group, and the model group were given distilled water by gavage for 15 consecutive days. According to body weight, six rats were randomly selected to take abdominal aortic blood for determination of serum anti-Mullerian hormone (AMH) content by enzyme-linked immunosorbent assay. According to body weight, six rats were randomly selected in the remaining rats to undergo high-frequency small animal ultrasound examination to measure ovarian volume and ovarian artery blood supply (resistance index and pulsatility index), and follicle count were measured. The female mice were fed with male mice at a ratio of 2:1 to observe the pregnancy rate, live fetus number, still fetus number, and absorbed fetus number. The weights of uterus and fetus were measured, while the placental weight, fetal weight, body length, and tail length were measured for live fetus. Bone and visceral malformations were also detected for live fetus. Results There were no significant differences in serum AMH and ovarian volume among the groups. Compared with the model group, the numbers of follicles in the blank group, the sham operation group, and the Huoxue Xiaoyi Formula low-, medium-, and high-dose groups were increased; compared with the Huoxue Xiaoyi Formula low-dose group, the numbers of follicles in the blank group and the Huoxue Xiaoyi Formula medium-dose group were increased (P<0.05). Compared with the model group, the resistance index and pulsatility index of ovarian artery blood flow in the blank group, the sham operation group, and the Huoxue Xiaoyi Formula low-, medium-, and high-dose groups were decreased(P<0.05). There was no significant difference in pregnancy rate among the groups. Compared with the model group and the Huoxue Xiaoyi Formula low-dose group, the live fetus number and the weight of uterus and fetus in the blank group, the sham operation group, and the Huoxue Xiaoyi Formula medium- and high-dose groups were increased (P<0.05). There were no significant differences in the still fetus number, absorbed fetus number, placental weight, fetal weight, body length and tail length among the groups. No visceral or skeletal malformations were found in the live fetal rats among the groups.Conclusion In endometriosis model rats, the ovarian artery blood flow perfusion is insufficient, and the follicle count is reduced, affecting ovary function, thereby reducing the live fetus number. After applying the Huoxue Xiaoyi Formula, it can improve ovarian blood supply, increase the follicle count, and increase the live fetus number. The effect of increasing the live fetus number with the medium- and high-doses of Huoxue Xiaoyi Formula is more significant, and there is no reproductive toxicity.

Sepsis is a condition characterized by organ dysfunction resulting from the systemic inflammatory response triggered by an infection. Excessive inflammation and immunosuppression are intertwined, and severe cases may even develop into multiple organ failure. Studies have shown that indoleamine 2,3-dioxygenase 1-mediated tryptophan metabolism is involved in the occurrence and development of sepsis, and elevated plasma kynurenine levels and Kyn/Trp ratios are early indicators of sepsis development. In this paper, we provide a comprehensive summary of the role of IDO1 in the acute inflammatory phase of sepsis, late immunosuppression, and organ damage. This includes its regulation of inflammatory state, immune cell function, blood pressure, and other aspects. Additionally, we analyze preclinical studies on targeted IDO1 drugs. An in-depth understanding and study of IDO may help to understand the pathogenesis and clinical significance of sepsis and multiple organ damage from a new perspective and provide new research ideas for exploring its prevention and treatment methods.

Objective:To investigate the effect of safflower yellow pigment injection combined with alprostadil on patients after coronary artery bypass grafting(CABG).Methods:A total of 92 patients with coronary heart disease who received CABG in Department of Cardiovascular Surgery,Handan Central Hospital between September 2018 and September 2020 were selected.According to order of admission,they were divided into control group(n=46,from September 2018 to Sep-tember 2019,routine therapy+alprostadil after CABG)and study group(n=46,from October 2019 to September 2020,safflower yellow pigment injection based on control group),both groups were treated for 28d.On 3d after drug withdraw-al,therapeutic effect,cardiac function indexes,four myocardial enzyme spectrum and perioperative indexes were compared between two groups.Results:On 3d after drug withdrawal,compared with control group,patients in study group had sig-nificant higher total effective rate(73.9％vs.91.3％),left ventricular ejection fraction(LVEF)[(55.77±4.48)％vs.(62.18±4.21)％](P=0.028,＜0.001),and significant lower left atrial diameter(LAD)[(36.83±3.45)mm vs.(32.09±3.23)mm],left ventricular end-diastolic diameter(LVEDd)[(49.04±4.65)mm vs.(43.83±5.24)mm],levels of creatine kinase(CK)[(125.13±14.21)U/L vs.(62.56±8.42)U/L],lactate dehydrogenase(LDH)[(203.58±31.63)U/L vs.(156.07±22.26)U/L],aspartate aminotransferase(AST)[(44.25±12.98)U/L vs.(35.41±12.37)U/L]and creatine kinase isoenzyme MB(CK-MB)[(28.11±9.84)U/L vs.(17.59±7.41)U/L](P＜0.001 all).Conclusion:The combination of safflower yellow pigment injection and alprostadil can improve the thera-peutic effect and heart function,and reduce myocardial injury in patients after CABG.

Activation of nuclear factor erythroid 2-related factor 2(Nrf2)by Kelch-like ECH-associated protein 1(Keap1)alkylation plays a central role in anti-inflammatory therapy.However,activators of Nrf2 through alkylation of Keap1-Kelch domain have not been identified.Deoxynyboquinone(DNQ)is a natural small molecule discovered from marine actinomycetes.The current study was designed to investigate the anti-inflammatory effects and molecular mechanisms of DNQ via alkylation of Keap1.DNQ exhibited signif-icant anti-inflammatory properties both in vitro and in vivo.The pharmacophore responsible for the anti-inflammatory properties of DNQ was determined to be the α,β-unsaturated amides moieties by a chemical reaction between DNQ and N-acetylcysteine.DNQ exerted anti-inflammatory effects through activation of Nrf2/ARE pathway.Keap1 was demonstrated to be the direct target of DNQ and bound with DNQ through conjugate addition reaction involving alkylation.The specific alkylation site of DNQ on Keap1 for Nrf2 activation was elucidated with a synthesized probe in conjunction with liquid chromatography-tandem mass spectrometry.DNQ triggered the ubiquitination and subsequent degra-dation of Keap1 by alkylation of the cysteine residue 489(Cys489)on Keap1-Kelch domain,ultimately enabling the activation of Nrf2.Our findings revealed that DNQ exhibited potent anti-inflammatory capacity through α,β-unsaturated amides moieties active group which specifically activated Nrf2 signal pathway via alkylation/ubiquitination of Keap1-Kelch domain,suggesting the potential values of targeting Cys489 on Keap1-Kelch domain by DNQ-like small molecules in inflammatory therapies.